Lentiviral infection (Human Immunodeficiency Virus in humans) and the progression to AIDS are associated with chronic generalized activation and dysfunction of the immune system thought to drive pathogenesis. To determine the initiation of chronic immune activation, we recently studied acute lentiviral infection in two species of nonhuman primate;African green monkeys (AGM), resistant to the development of AIDS, and pigtailed macaques (PM), susceptible to the development of AIDS. We found that the earliest determinant of resistance or susceptibility to disease progression was the kinetic of the early innate antiviral response characterized by IFNa production: IFNa production was initiated in both species and remained elevated in PM, but was rapidly quenched in AGM. We hypothesize that this differential acute response to SIV infection is due to inherent differences in the detection of lentiviruses by the innate immune system in AGM and PM. This proposal investigates the mechanisms of lentiviral detection in the absence of infection in the AGM and PM as well as investigating the relationship between innate antiviral responses and the lack of disease in populations of HIV controllers. PUBLIC HEALTH RELEVANCE: HIV infection causes widespread persistent inflammation that leads to the progressive loss of function in the immune system and the onset of AIDS. This proposal investigates the mechanisms of persistent inflammation during HIV infection with the goal of defining targets for therapeutic intervention.